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Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial compound, \u2018Calxinin\u2019. A compound that consists of hydroxyethylamine (HEA) and trifluoromethyl-benzyl-piperazine. Calxinin exhibits potent inhibitory activity in the nanomolar range against the asexual blood stages of drug-sensitive (3D7), multidrug-resistant (Dd2), artemisinin-resistant (IPC4912), and fresh Kenyan field isolated Plasmodium falciparum strains. Calxinin treatment resulted in diminished maturation of parasite sexual precursor cells (gametocytes) accompanied by distorted parasite morphology. Further, in vitro liver-stage testing with a mouse model showed reduced parasite load at an IC50 of 79 nM. A single dose (10 mg\/kg) of Calxinin resulted in a 30% reduction in parasitemia in mice infected with a chloroquine-resistant strain of the rodent parasite P. berghei. The ex vivo ookinete inhibitory concentration within mosquito gut IC50 was 150 nM. Cellular in vitro toxicity assays in the primary and immortalized human cell lines did not show cytotoxicity. A computational protein target identification pipeline identified a putative P. falciparum membrane protein (Pf3D7_1313500) involved in parasite calcium (Ca2+) homeostasis as a potential Calxinin target. This highly conserved protein is related to the family of transient receptor potential cation channels (TRP-ML). Target validation experiments showed that exposure of parasitized RBCs (pRBCs) to Calxinin induces a rapid release of intracellular Ca2+ from pRBCs; leaving de-calcinated parasites trapped in RBCs. Overall, we demonstrated that Calxinin is a promising antimalarial lead compound with a novel mechanism of action and with potential therapeutic, prophylactic, and transmission-blocking properties against parasites resistant to current antimalarials.<\/jats:p>","DOI":"10.3390\/pharmaceutics14071371","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"1371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3002-1315","authenticated-orcid":false,"given":"Yash","family":"Gupta","sequence":"first","affiliation":[{"name":"Infectious Diseases, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7239-6345","authenticated-orcid":false,"given":"Neha","family":"Sharma","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, New Delhi 110021, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0319-8887","authenticated-orcid":false,"given":"Snigdha","family":"Singh","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, New Delhi 110021, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesus G.","family":"Romero","sequence":"additional","affiliation":[{"name":"Stritch School of Medicine, Loyola University Chicago, Chicago, IL 60660, USA"},{"name":"School of Biology, Institute of Experimental Biology, Central University of Venezuela, Caracas 1040, Venezuela"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1453-1139","authenticated-orcid":false,"given":"Vinoth","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry 605014, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6454-1613","authenticated-orcid":false,"given":"Reagan M.","family":"Mogire","sequence":"additional","affiliation":[{"name":"Centre Clinical Research, Kenya Medical Research Institute, Nairobi P.O. Box 54840-00200, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Kashif","sequence":"additional","affiliation":[{"name":"Infectious Diseases Laboratory, National Institute of Immunology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Beach","sequence":"additional","affiliation":[{"name":"Stritch School of Medicine, Loyola University Chicago, Chicago, IL 60660, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Jeske","sequence":"additional","affiliation":[{"name":"Stritch School of Medicine, Loyola University Chicago, Chicago, IL 60660, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-1057","authenticated-orcid":false,"family":"Poonam","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Miranda House, University of Delhi, New Delhi 110021, India"},{"name":"Delhi School of Public Health, Institute of Eminence, University of Delhi, New Delhi 110007, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhards R.","family":"Ogutu","sequence":"additional","affiliation":[{"name":"Centre Clinical Research, Kenya Medical Research Institute, Nairobi P.O. Box 54840-00200, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan M.","family":"Kanzok","sequence":"additional","affiliation":[{"name":"Department of Biology, Loyola University Chicago, Chicago, IL 60660, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8584-2706","authenticated-orcid":false,"given":"Hoseah M.","family":"Akala","sequence":"additional","affiliation":[{"name":"Centre Clinical Research, Kenya Medical Research Institute, Nairobi P.O. 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